((thioxanthenyl)propyl)-triazaspiro(4,5)decan-4-ones

ABSTRACT

The compounds, 1-phenyl-8-(3-(9-thioxanthenyl)-propyl)-1,3,8triazaspiro(4,5)decan-4-one, and 1-phenyl-8-(3-(thioxanthen-9ylidene)propyl)-1,3,8-triazaspiro-(4,5)decan-4 -one, useful as neuroleptic agents.

United States Patent 1191 Soudijn et a1.

1 1 [(TIIIOXANTHENYL) PROPYL]-TRIAZASPIRO[4,5]DECAN- 4-ONES [751 Inventors: Willem Soudijn, Turnhout; Ineke Van Wijngaarden, Beerse; Paul Adrian Jan .Ianssen, Vosselaar, all of Belgium [731 Assignee: Janssen Pharmaceutica, N.V.,

Beerse, Belgium [22] Filed: Feb. 26, 1973 [21] App], No.: 335,846

[52] US. Cl. 260/240 TC, 424/267, 260/293.57,

FOREIGN PATENTS OR APPLICATIONS 42-24589 11/1967 Japan .1 260/243 A 2,163,657 7/1972 Germany 260/240 TC OTHER PUBLICATIONS Chemical Abstracts, Vol. 69, Abst. No. 67,440m (abst. of Japanese Patent 42-24589 above cited) (1968). Chemical Abstracts, Vol. 77, Abst, No. 139838n (abst. of German Offen. 2,163,657 pub. July 13, (1972).

Chemical Abstracts, Vol. 70, Abst. No. 7714911 (1969) (abst. of Lecolier, Chim. Ther. 1968, 3(3), pp. 193-199.

Primary Examiner-John D. Randolph Attorney, Agent, or Firm-Salvatore R. Conte [57] ABSTRACT The compounds, 1-pheny1-8-[3-( 9 lhioxanthenyl)- propyl]- l ,3 ,8-triazaspiro[4,5 ]decan-4-0ne, and 1 pheny1-8-[3-(thioxanthen-9-y1idene)propyl]-1,3,8- triaZaspiro-[4,5]decan-4-one, useful as neuroleptic agents.

3 Claims, No Drawings [(THIOXANTHENYL) PROPYL -TRIAZASPIRO[4,5lDECAN-4-ONES DESCRIPTION OF THE INVENTION This invention relates to novel triazaspiro [4,5]decan-4-one derivatives, namely, l-phenyl-8-[3-(9- thioxanthenyl)-propyl]-l ,3 ,8-triazaspiro[4,5 ]decan- 4-one, having the formula:

and l,3,8-triazaspiro[4,5]decan -4-one having the formula:

including the therapeutically active non-toxic acid addition salts thereof.

The compounds of formula l-a) and l-b) are prepared by reacting the respective derivatives of formulas ll-a) and Il-b), wherein Xis a reactive ester of the corresponding alcohol, e.g., chloro, bromo, mesylate, tosylate, and the like, preferably chloro or bromo, with l-phenyl-l ,3,8-triazaspiro[4,5]decan-4-one III). This condensation reaction is conveniently conducted in an inert organic solvent such as, for example, an aromatic hydrocarbon, e.g., benzene, toluene, xylene and the like; a lower alkanol, e.g., methanol, ethanol, n-butanol and the like; a ketone, e.g., 4-methyl-2-pentanone, bu-

l-phenyl-8-[ 3-( thioxanthenl -ylidene)propyl tanone, and the like; an ether, e.g., dioxane, diethyl ether and the like; dimethylformamide (DMF); nitrobenzene; and the like. The addition of an acid acceptor, i.e., an appropriate base such as, for example, an alkali metal carbonate or bicarbonate, or an organic tertiary amine such as, for example, a trialkylamine, e.g., triethylamine, tributylamine and the like, or a heterocyclic amine, e.g., pyridine, quinoline and the like, may be utilized to bind the acid that is liberated during the course of the reaction. The amount of acid acceptor that may be employed is not critical, but, for optimum conditions, the theoretical number of moles of liberated acid can easily be calculatedfrom the quantities of reactants employed and, thus, the corresponding amount of acid acceptor that need be employed can readily be determined. The presence of catalytic amounts of potassium iodide is also desirable, when X is halo. Elevated temperatures may be employed to enhance the rate of reaction.

The compounds of formula (1-21) and (I-b) may be converted to the therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid, such as, for example, an inorganic acid, such as a hydrohalic acid, e.g., hydrochloric, hydrobromic, and the like, and sulfonic acid, nitric acid, phosphoric acid and the like; or an organic acid, such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric,benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfonic, salicyclic, p-aminosalicyclic and the like CHZ-CHZ-CHZ-X (II-a) (111) Q CK NH CH-CH -CH -X HN (1-11) 2 z (ll-b) (1n) acids. Conversely, the salt form can be converted by treatment with alkali into the free base form.

The subject compounds and the therapeutically active acid addition salts thereof have been found to possess central nervous system (CNS) depressant activity similar to the neuroleptic activity of butyrophenones, for example, haloperidol (see US. Pat. No. 3.438.991) and of certain triazaspiro[4,5]decan-4-ones, e.g., fluspirilene (see US. Pat. No. 3.238.216) and of the 4-aryl-4-hydroxypiperidines in US. Pat. No. 3.579.990. Although the subject compounds are qualitatively similar in neuroleptic activity to haloperidol, they differ significantly from the latter in their longer duration of action, similar to said fluspirilene and to said 4-aryl-4-hydroxypiperidines.

Neuroleptic drugs are known to block apomorphineinduced vomiting in dogs. In the anti-apomorphine test [see Method l. in Janssen, P. A. J. et al., Arzneim- Forsch., 15, 1196 (1965)], the compound to be tested is given orally followed at different time intervals thereafter by the standard dose of apomorphine (0.31 mg/kg s.c.) which will induce vomiting in untreated dogs. Anti-apomorphine activity is demonstrated with the subject compounds and salts thereof at oral dose levels as low as 0.005 mg/kg and at ED values of about 0.021.0 mg/kg orally. The ED value (in mg/kg) is the oral dose level of the tested compound protecting 50 percent of the animals from emesis. In Table 1, the

ED values and the long duration of activity of compounds exemplified hereinafter are given.

Another characterization of neuroleptic drugs is their ability to antagonize amphetamine-induced CNS- stimulation. In the amphetamine antagonism test, male Wistar rats are pretreated with an oral dose of the compound to be tested and challenged one hour thereafter with a standard dose of amphetamine (5 mg/kg i.v.)..ln untreated animals, the standard dose of amphetamine will induce typical CNS-stimulation, e.g., agitation and stereotyped chewing. These phenomena are antagonized by neuroleptic drugs, and, with the subject compounds, such antagonism is observed at oral dose levels of from about 0.05 to about 5.0 mg/kg-The data in Table 1 shows the oral dose levelsat which compounds exemplified hereinafter protect the rats against the amphetamine-induced agitation and chewing.

The following examples are intended to illustrate, but not to limit, the scope of the present invention. Unless otherwise stated, all parts are by weight.

EXAMPLE 1 A mixture of 1.54 parts of 9-(3-chloropropyl)- thioxanthene, 1.16 parts of l-phenyl-l,3,8-triazaspiro [4,5]decan-4-one, 0.8 parts of anhydrous sodium carbonate, 0.1 parts of potassium iodide and 9.5 parts of dimethylformamide is stirred and heated at 105C in an oil-bath for 20 hours. The reaction mixture is cooled and water is added. The precipitated product is filtered off, washed with water, dried and recrystallized from acetone, yielding 1-phenyl-8-[ 3- 9- thioxanthenyl)propyl]-1,3,8-triazaspiro[4,5]decan- 4-one; mp. 252.lC.

EXAMPLE [I A mixture of 2.32 parts of 9-( 3-bromopropylidene)- thioxanthene, 3.5 parts of 1-phenyl-1,3 ,8- triazaspiro[4,5]-decan-4-one, 1.6 parts of sodium carbonate and 20 parts of dimethylformamide is stirred for 3hr.30min. in an oil-bath at 1l0l 15C. The reaction mixture is cooled and diluted with water. The whole is stirred for 1hr.30min. at room temperature. The precipitated product is filtered off, washed with water, dried and purified by column-chromatography, using a mixture of chloroform and 10 percent of methanol. The pure fractions are collected and the solvent is evaporated. The residue of l-phenyl-8-[3- thioxanthen-9-ylidene)propyl]-1,3,8- triazaspiro[4,5]decan-4-one is converted into the hydrochloride salt in methanol and 2-propanol. The crude salt is filtered off, crystallized from acetone and dried in vacuo at C, yielding l-phenyl-8-[3- thioxanthen-9-ylidene)propyl]-1 ,3,8;triazaspiro- [4,5]decan-4-one hydrochloride; mp. 249.5257C.

We claim:

l. A chemical compound selected from the group consisting of l-phenyl-8-[3-( 9-thioxanthenyl)propyl]- 1,3,8-triazaspiro[4,5 ]decan-4-one; l-phenyl-8-[ 3- thioxanthen-9-ylidene)propyl]-1,3,8-triazaspiro[4,5]- decan-4-one; and the therapeutically active acid addition salts thereof.

' 2. 1-phenyl-8-[3-(9-thioxanthenyl)propyl]-1,3,8- triazaspiro[4,5 ]decan-4-one.

3. 1-phenyl-8-[3-( thioxoanthen-9-ylidene )-'propyl]- 1 ,3 ,8-triazaspiro[4,5 ]decan-4-one.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3. 8 8 635 Dated October 22, 197

Inventor(s) Willem SOudijn, et 8.].

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

fi In Column 2, line 66, "3. 579. 990 should read r 3,575, 99

Signed and sealed this 13th day of May 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks 

1. A CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-PHENYL-8-(3-(9-THIOXANTHENYL)PROPYL)-1,3,8TRIAZASPIROL(4,5)DECAN-4-ONE; 1-PHENYL-8-(3-(THIOXANTHEN-9YLIDENE)PROPYL)-1,3,8-TRIAZASPIROL(4,5)-DECAN-4 -ONE; AND THE THERAPEUTICALLY ACTIVE ACID ADDITION SALTS THEREOF.
 2. 1-phenyl-8-(3-(9-thioxanthenyl)propyl)-1,3,8-triazaspiro(4, 5)decan-4-one.
 3. 1-phenyl-8-(3-(thioxoanthen-9-ylidene)-propyl)-1,3,8-triazaspiro(4,5)decan-4-one. 